Swine flu, antivirals & proteins

With 14 more cases of swine flu announced at the weekend, the number of confirmed cases in the UK has reached over 100. With another 155 possible cases still under investigation, this is likely to continue to rise steadily in the next days and weeks.

Thankfully, the spread of the virus seems to be contained to some extent. That may be down to various things, such as the time of year, how easily it’s passed on, people’s awareness of swine flu and its symptoms, their willingness to get in touch with their GP and stay at home, and the antivirals given to those affected.

While we may have to wait until the autumn and flu season before we will know more about how this outbreak will run its course, how will the antiviral drugs Tamiflu and Relenza help us?

‘These antivirals definitely work,’ says Professor Elspeth Garman of the Department of Biochemistry. She co-authored an influential paper in Science in 2001 calling for countries to stockpile the drugs in advance of an increasingly likely flu pandemic. ‘As long as they are taken at the beginning of an infection (within 48 hours of evident symptoms), they will stop the flu virus in its tracks.’

‘Relenza, made by GlaxoSmithKline, is a nasal spray, while Roche’s Tamiflu is taken as a pill,’ she explains. ‘This makes Tamiflu easier to take, which is important if large numbers of people will be given it, but mutations to Tamiflu can more easily arise that will make flu resistant to the drug. However, it is still very likely to be effective in any pandemic.’

A flu virus has lots of protein molecules on its surface which come in two types: H and N. There are various subtypes of H and N proteins, which gives each strain of influenza A its name: e.g. H5N1 for bird flu and H1N1 for swine flu. The H proteins act like Velcro, and flu infections start when viruses cling to receptors on cells in the top of the throat using the H protein. The cells are taken over and used to produce more viruses before the cells eventually burst and die.

But for the newly-made viruses to go on and infect other cells in the body, the viruses have to be released from the dead cell by chopping off the receptors on the outside of the dead cell to stop the Velcro-like H proteins sticking to them. This is what the N proteins do: they snip the receptors to allow further infection of other cells. It’s this step that Tamiflu and Relenza prevent. The drugs bind to the N proteins and stop them snipping the receptors on throat cells, with the result that infection of further cells in the body is largely stopped.

Professor Garman’s group has been involved in determining the structure of different N proteins from various strains of flu. By building a 3D picture of the proteins using a technique called X-ray crystallography, they can see the crucial pocket where the antiviral drugs bind in atomic detail. This approach was used in designing the drugs in the first place, and gives a good understanding of whether the drugs will work with other N proteins beyond N1.

‘We’re currently working with a colleague at the National University of Mexico on an N6 protein from a flu virus in an English duck,’ says Professor Garman. ‘This connection with Mexico where this swine flu outbreak began is entirely coincidental, but it does bring home the relevance of all of this. There are also two Mexican graduate students currently working in my lab. Thankfully, their family and friends are all fine.’

With antiviral drugs that work, concern shifts slightly. ‘With these antiviral drugs in hand, a pandemic becomes less of a science issue and more a public health problem,’ Professor Garman says. ‘It becomes all about stockpiles of the drugs and distribution in the event of a pandemic.'

Developing countries will find this a problem, as keeping large stockpiles is expensive and who do you give access to the scarce tablets? This is an issue Greg Katz picked up, writing for the Associated Press.

The other problem Professor Garman highlights is picking up swine flu, or any other flu strain, early enough. ‘What we really need is a quick, cheap, over-the-counter test to pick up whether people have flu early on. That way we can distribute antivirals only to those that really do have the disease.’